Ischemic stroke is a major cause of death and long-term disability in the United States. Approved therapy is limited to a thrombolytic agent. Understanding the mechanisms of neuronal death, which is a goal of this study, will provide new therapeutic strategies for stroke treatment. Oxidative stress, generated during cerebral ischemia and reperfusion, is associated with the signaling pathways that lead to neuronal survival or death by apoptosis and/or necrosis, depending on the severity and duration of ischemic insults. We have recently demonstrated in experimental animals that oxidative- stress-sensitive signaling pathways, like phosphatidylinositol 3-kinase (PI3-K) and Akt (protein kinase B), and nuclear factor-kappa B (NF-icB), are involved in neuronal survival or death after cerebral ischemia and reperfusion. Our preliminary studies have established a direct link between PI3-K/Akt signaling and NF-KB activation in neuronal survival after mild ischemic insult, whereas during severe ischemic insult, NF-KB activity is associatedwith high levels of oxidative stress, which leads to neuronal death. We now hypothesize that oxidative stress and PI3-K/Akt act in concert to modulate NF-KB activity, which determines the survival or death outcome of ischemic neurons. Our specific aims are: 1) To elucidate the mechanisms underlying PI3-K/Akt signaling and NF-KB activity in neuronal survival after transient focal cerebral ischemia. 2) To elucidate the role of oxidative stress during reperfusion after severe ischemia in death signaling, and the involvement of NF-KB activity. 3) To study the interplay between mitochondrial oxidative stress and survival signaling as a biochemical/molecular switch for ischemic neuronal death and survival. We believe these are unique and fresh approaches that will provide insights into the oxidative mechanisms involved in the pathogenesis of apoptosis after cerebral ischemia and reperfusion.